Single-nucleus transcriptomics of the prefrontal cortex in major depressive disorder implicates oligodendrocyte precursor cells and excitatory neurons

Major depressive disorder (MDD) has an enormous impact on global disease burden, affecting millions of people worldwide and ranking as a leading cause of disability for almost three decades. Past molecular studies of MDD employed bulk homogenates of postmortem brain tissue, which obscures gene expre...

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Published in:	Nature neuroscience Vol. 23; no. 6; pp. 771 - 781
Main Authors:	Nagy, Corina, Maitra, Malosree, Tanti, Arnaud, Suderman, Matthew, Théroux, Jean-Francois, Davoli, Maria Antonietta, Perlman, Kelly, Yerko, Volodymyr, Wang, Yu Chang, Tripathy, Shreejoy J, Pavlidis, Paul, Mechawar, Naguib, Ragoussis, Jiannis, Turecki, Gustavo
Format:	Journal Article
Language:	English
Published:	United States Nature Publishing Group 01.06.2020
Subjects:	Adolescent Adult Aged Aged, 80 and over Brain Case-Control Studies Depressive Disorder, Major - metabolism Gene expression Gene Regulatory Networks Glial stem cells High-Throughput Nucleotide Sequencing - methods Hormones Humans Immune response Male Mental depression Middle Aged Neurons Neurons - metabolism Nuclei (cytology) Oligodendrocyte Precursor Cells - metabolism Oligodendrocytes Precursors Prefrontal cortex Prefrontal Cortex - metabolism Steroid hormones Steroids Synaptic plasticity Transcriptome Young Adult
ISSN:	1097-6256, 1546-1726, 1546-1726
Online Access:	Get full text
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Abstract	Major depressive disorder (MDD) has an enormous impact on global disease burden, affecting millions of people worldwide and ranking as a leading cause of disability for almost three decades. Past molecular studies of MDD employed bulk homogenates of postmortem brain tissue, which obscures gene expression changes within individual cell types. Here we used single-nucleus transcriptomics to examine ~80,000 nuclei from the dorsolateral prefrontal cortex of male individuals with MDD (n = 17) and of healthy controls (n = 17). We identified 26 cellular clusters, and over 60% of these showed differential gene expression between groups. We found that the greatest dysregulation occurred in deep layer excitatory neurons and immature oligodendrocyte precursor cells (OPCs), and these contributed almost half (47%) of all changes in gene expression. These results highlight the importance of dissecting cell-type-specific contributions to the disease and offer opportunities to identify new avenues of research and novel targets for treatment.
AbstractList	Major depressive disorder (MDD) has an enormous impact on global disease burden, affecting millions of people worldwide and ranking as a leading cause of disability for almost three decades. Past molecular studies of MDD employed bulk homogenates of postmortem brain tissue, which obscures gene expression changes within individual cell types. Here we used single-nucleus transcriptomics to examine ~80,000 nuclei from the dorsolateral prefrontal cortex of male individuals with MDD (n = 17) and of healthy controls (n = 17). We identified 26 cellular clusters, and over 60% of these showed differential gene expression between groups. We found that the greatest dysregulation occurred in deep layer excitatory neurons and immature oligodendrocyte precursor cells (OPCs), and these contributed almost half (47%) of all changes in gene expression. These results highlight the importance of dissecting cell-type-specific contributions to the disease and offer opportunities to identify new avenues of research and novel targets for treatment. Major depressive disorder (MDD) has an enormous impact on global disease burden, affecting millions of people worldwide and ranking as a leading cause of disability for almost three decades. Past molecular studies of MDD employed bulk homogenates of postmortem brain tissue, which obscures gene expression changes within individual cell types. Here we used single-nucleus transcriptomics to examine ~80,000 nuclei from the dorsolateral prefrontal cortex of male individuals with MDD (n = 17) and of healthy controls (n = 17). We identified 26 cellular clusters, and over 60% of these showed differential gene expression between groups. We found that the greatest dysregulation occurred in deep layer excitatory neurons and immature oligodendrocyte precursor cells (OPCs), and these contributed almost half (47%) of all changes in gene expression. These results highlight the importance of dissecting cell-type-specific contributions to the disease and offer opportunities to identify new avenues of research and novel targets for treatment.Major depressive disorder (MDD) has an enormous impact on global disease burden, affecting millions of people worldwide and ranking as a leading cause of disability for almost three decades. Past molecular studies of MDD employed bulk homogenates of postmortem brain tissue, which obscures gene expression changes within individual cell types. Here we used single-nucleus transcriptomics to examine ~80,000 nuclei from the dorsolateral prefrontal cortex of male individuals with MDD (n = 17) and of healthy controls (n = 17). We identified 26 cellular clusters, and over 60% of these showed differential gene expression between groups. We found that the greatest dysregulation occurred in deep layer excitatory neurons and immature oligodendrocyte precursor cells (OPCs), and these contributed almost half (47%) of all changes in gene expression. These results highlight the importance of dissecting cell-type-specific contributions to the disease and offer opportunities to identify new avenues of research and novel targets for treatment. Major depressive disorder (MDD) has an enormous impact on global disease burden, affecting millions of people worldwide and ranking as a leading cause of disability for almost three decades. Past molecular studies of MDD employed bulk homogenates of postmortem brain tissue, which obscures gene expression changes within individual cell types. Here we used single-nucleus transcriptomics to examine ~80,000 nuclei from the dorsolateral prefrontal cortex of male individuals with MDD (n = 17) and of healthy controls (n = 17). We identified 26 cellular clusters, and over 60% of these showed differential gene expression between groups. We found that the greatest dysregulation occurred in deep layer excitatory neurons and immature oligodendrocyte precursor cells (OPCs), and these contributed almost half (47%) of all changes in gene expression. These results highlight the importance of dissecting cell-type-specific contributions to the disease and offer opportunities to identify new avenues of research and novel targets for treatment.Single-nucleus transcriptomics reveal brain alterations associated with major depression. Deep layer excitatory cells and immature oligodendrocytes showed most changes, involving synaptic plasticity, immune function and steroid hormones.
Author	Wang, Yu Chang Nagy, Corina Yerko, Volodymyr Maitra, Malosree Perlman, Kelly Suderman, Matthew Tripathy, Shreejoy J Mechawar, Naguib Davoli, Maria Antonietta Tanti, Arnaud Théroux, Jean-Francois Ragoussis, Jiannis Pavlidis, Paul Turecki, Gustavo
Author_xml	– sequence: 1 givenname: Corina surname: Nagy fullname: Nagy, Corina organization: McGill Group for Suicide Studies, Douglas Mental Health University Institute, Montreal, Quebec, Canada – sequence: 2 givenname: Malosree surname: Maitra fullname: Maitra, Malosree organization: McGill Group for Suicide Studies, Douglas Mental Health University Institute, Montreal, Quebec, Canada – sequence: 3 givenname: Arnaud surname: Tanti fullname: Tanti, Arnaud organization: McGill Group for Suicide Studies, Douglas Mental Health University Institute, Montreal, Quebec, Canada – sequence: 4 givenname: Matthew surname: Suderman fullname: Suderman, Matthew organization: MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK – sequence: 5 givenname: Jean-Francois surname: Théroux fullname: Théroux, Jean-Francois organization: McGill Group for Suicide Studies, Douglas Mental Health University Institute, Montreal, Quebec, Canada – sequence: 6 givenname: Maria Antonietta surname: Davoli fullname: Davoli, Maria Antonietta organization: McGill Group for Suicide Studies, Douglas Mental Health University Institute, Montreal, Quebec, Canada – sequence: 7 givenname: Kelly surname: Perlman fullname: Perlman, Kelly organization: McGill Group for Suicide Studies, Douglas Mental Health University Institute, Montreal, Quebec, Canada – sequence: 8 givenname: Volodymyr surname: Yerko fullname: Yerko, Volodymyr organization: McGill Group for Suicide Studies, Douglas Mental Health University Institute, Montreal, Quebec, Canada – sequence: 9 givenname: Yu Chang surname: Wang fullname: Wang, Yu Chang organization: McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada – sequence: 10 givenname: Shreejoy J surname: Tripathy fullname: Tripathy, Shreejoy J organization: Department of Psychiatry, McGill University, Montreal, Quebec, Canada – sequence: 11 givenname: Paul surname: Pavlidis fullname: Pavlidis, Paul organization: Michael Smith Laboratories and Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada – sequence: 12 givenname: Naguib surname: Mechawar fullname: Mechawar, Naguib organization: Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada – sequence: 13 givenname: Jiannis orcidid: 0000-0002-8515-0934 surname: Ragoussis fullname: Ragoussis, Jiannis organization: McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada – sequence: 14 givenname: Gustavo orcidid: 0000-0003-4075-2736 surname: Turecki fullname: Turecki, Gustavo email: gustavo.turecki@mcgill.ca, gustavo.turecki@mcgill.ca, gustavo.turecki@mcgill.ca organization: Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada. gustavo.turecki@mcgill.ca
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/32341540$$D View this record in MEDLINE/PubMed
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Snippet	Major depressive disorder (MDD) has an enormous impact on global disease burden, affecting millions of people worldwide and ranking as a leading cause of...
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SubjectTerms	Adolescent Adult Aged Aged, 80 and over Brain Case-Control Studies Depressive Disorder, Major - metabolism Gene expression Gene Regulatory Networks Glial stem cells High-Throughput Nucleotide Sequencing - methods Hormones Humans Immune response Male Mental depression Middle Aged Neurons Neurons - metabolism Nuclei (cytology) Oligodendrocyte Precursor Cells - metabolism Oligodendrocytes Precursors Prefrontal cortex Prefrontal Cortex - metabolism Steroid hormones Steroids Synaptic plasticity Transcriptome Young Adult
Title	Single-nucleus transcriptomics of the prefrontal cortex in major depressive disorder implicates oligodendrocyte precursor cells and excitatory neurons
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